This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The specific aims of this study are to determine the pharmacokinetics and tolerability of long term ceftriaxone treatment, and to subsequently determine the efficacy of this treatment in ALS patients. Amyotrophic lateral sclerosis is a uniformly progressive and fatal neurodegenerative disorder for which there is no known cure. In a novel attempt to widen the search for potential therapeutic agents, an NINDS led cooperative group performed an in-vitro screening program of 1040 FDA approved drugs in over 28 assays relevant to various neurodegenerative disorders. Several cephalosporins showed potential for improving survival in ALS patients. Phase 1 and 2 of this study will determine optimal dose, safety and preliminary efficacy in ALS. Sixty patients (8 at WFUBMC) will be enrolled into the phase I/II study, including a placebo group and two groups receiving either 2 or 4 grams of ceftriaxone daily. Both pharmacokinetic information and tolerability will be obtained. Based on these data, an assessment will be made as to whether a safe dose can be given to ALS patients that will produce CSF levels reasonably expected to produce a biologic effect. After 60 patients have completed at least 4 months of treatment, a decision whether to continue to a phase III study will be made. This phase of the trial will enroll an additional 540 patients (7 at WFUBMC) from 40 sites. The patients will be randomized to placebo or ceftriaxone and followed monthly for safety and efficacy. The main outcome measure will be survival between the two groups.